Process for the preparation of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and its non-toxic salts

ABSTRACT

6-Methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide is prepared by reaction of acetoacetamide with at least approximately twice the molar amount of SO 3  per mole of acetoacetamide, if appropriate in an inert inorganic or organic solvent. Relevant salts can be obtained, using bases, from the product which results in the form of the acid. 
     The non-toxic salts, in particular the potassium salt, are valuable synthetic sweeteners.

This application is a continuation of application Ser. No. 714,175,filed Mar. 20, 1985, now U.S. Pat. No. 4,563,521.

6-Methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2dioxide is the compoundof the formula ##STR1## As a consequence of the acidic hydrogen on thenitrogen atom, the compound is able to form salts (with bases). Thenon-toxic salts, such as, for example, the Na, the K and the Ca salt,can, because of their sweet taste, which is intense in some cases, beused as sweeteners in the foodstuffs sector, the K salt ("Acesulfame K"or just "Acesulfame") being of particular importance.

A number of different processes is known for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts; see Angewandte Chemie 8,5, Issue 22 (1973) pages 965 to73, corresponding to International Edition Vol. 12, No. 11 (1973), pages869-76. Virtually all the processes start from chloro- or fluorosulfonylisocyanate (XSO₂ NCO with X=Cl or F). The chloro- or fluorosulfonylisocyanate is then reacted with monomethylacetylene, acetone,acetoacetic acid, tert.butyl acetoacetate or benzyl propenyl ether(usually in a multistage reaction) to give acetoacetamide-N-sulfonylchloride or fluoride which, under the action of bases (such as, forexample, methanolic KOH), is cyclized and provides the correspondingsalts of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide. Wheredesired, the free oxathiazinone can be obtained from the salts in acustomary manner (with acids).

Another process for the preparation of the oxathiazinone intermediateacetoacetamide-N-sulfonyl fluoride starts from sulfamoyl fluoride H₂NSO₂ F, which is the partial hydrolysis product of fluorosulfonylisocyanate (German Offenlegunqsschrift No. 2,453,063). The fluoride ofsulfamic acid H₂ NSO₂ F is then reacted with an approximately equimolaramount of the acetoacetylating agent diketene, in an inert organicsolvent, in the presence of an amine, at temperatures between about -30°and 100° C.; the reaction takes place in accordance with the followingequation (with triethylamine as the amine): ##STR2##

Acetoacetamide-N-sulfonyl fluoride

The acetoacetamide-N-sulfonyl fluoride is then cyclized in a customarymanner using a base, for example using methanolic KOH, to the sweetener:##STR3##

Although some of the known processes provide quite satisfactory yieldsof 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts (up to about 85% of theory based on the startingsulfamoyl halide), they are still in need of improvement, particularlyfor industrial purposes, because of the necessity of using chloro- orfluorosulfonyl isocyanate, which are not very easy to obtain, asstarting materials; this is because the preparation of the chloro- andfluorosulfonyl isocyanate requires considerable precautionary measuresand safety arrangements by reason of the starting materials (HCN, Cl₂,SO₃ and HF), some of which are rather unpleasant to handle. Thepreparation of the chloro- and fluorosulfonyl isocyanate are based onthe following reaction equations:

    HCN+Cl.sub.2 →ClCN+HCl

    ClCN+SO.sub.3 →ClSO.sub.2 NCO

    ClSO.sub.2 NCO+HF→FSO.sub.2 NCO+HCl

Replacement of the sulfamoyl fluoride in the process according to theabovementioned German Offenlegungsschrift No. 2,453,063 by, for example,the considerably more easily obtainable (for example from NH₃ +SO₃)sulfamic acid H₂ NSO₃ H or its salts hardly appeared promising becausethe reaction of Na sulfamate H₂ NSO₃ Na with diketene in anaqueous-alkaline solution does not provide any reaction product whichcan be isolated pure. Rather, it has been possible to obtain the 1:1adduct, which is probably at least partially formed in this reaction,only in the form of the coupling product with 4-nitrophenyldiazoniumchloride, as a pale yellow dyestuff; see Ber. 83 (1950), pages 551-558,in particular page 555, last paragraph before the description of theexperiments, and page 558, last paragraph: ##STR4##

Moreover, the acetoacetamide-N-sulfonic acid has otherwise beenpostulated only, or also, as an intermediate in the decomposition of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide during boilingin aqueous solution; see the literature cited in the introduction,Angew. Chemie (1973) loc. cit.: ##STR5##

Thus, because the state of the art processes for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts are, in particular, not entirely satisfactory for beingcarried out on an industrial scale, in particular as a result of thenecessity to use starting materials which are not very straightforwardto obtain, the object was to improve the known processes appropriatelyor to develop a new improved process.

This object has been achieved according to the invention by the reactionof acetoacetamide with at least aporoximately twice the molar amount ofSO₃.

Thus, the invention relates to a process for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts, starting from an acetoacetyl compound; the processcomprises reacting acetoacetamide with at least approximately twice themolar amount of SO₃, where appropriate in an inert inorganic or organicsolvent, and then, where appropriate, also neutralizing with a base the6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide which isproduced in the form of the acid in this reaction.

During the reaction, it is probable that acetoacetamide-N-sulfonic acidis formed initially, from 1 mole of acetoacetamide and one mole of SO₃,and is then cyclized with another mole of SO₃ to give6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide: ##STR6##

The yields obtained in this reaction are about 30 to about 90% of theorybased on acetoacetamide. The process represents a considerable advancein this area, in particular because the starting materials are simpleand reasonably priced, and the reaction is extremely straightforward tocarry out.

It was very surprising that the reaction took place, in particular thering closure reaction, because the cyclization, which results in onemole of water being eliminated per mole of acetoacetamide-N-sulfonicacid, does not take place or, at any rate, virtually does not take placewith other agents which eliminate water, such as, for example, P₂ O₅,acetic anhydride, trifluoroacetic anhydride, thionyl chloride etc.

Acetoacetamide can be obtained from, for example, acetoacetyl chlorideor diketene and NH₃ and is, moreover, a readily available commercialproduct.

The acetoacetamide is then reacted with at least approximately twice themolar amount of SO₃ (per mole of acetoacetamide). The amount of SO₃ ispreferably about 2 to 20 moles, in particular about 4 to 10 moles, permole of acetoacetamide. It can be added to the reaction mixture eitherin the solid or liquid form or by condensing in SO₃ vapor. However, themore usual mode of addition comprises the addition of a solution of SO₃in concentrated sulfuric acid, liquid SO₂ or an inert organic solvent.

It is also possible to use reactive SO₃ derivatives which eliminate SO₃.It is particularly favorable for the course of the reaction to replacepart of the free SO₃ by a reactive SO₃ derivative. Examples of suchreactive SO₃ derivatives are adducts of SO₃ with tertiary amines orN-alkyl-substituted carboxamides, preferably those tertiary amines inwhich each N atom has up to 20, in particular up to only 10, carbonatoms. The following tertiary amines may be mentioned as examples:

Trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine,tri-n-butylamine, triisobutylamine, tricyclohexylamine,ethyldiisopropylamine, ethyldicyclohexylamine, N,N-dimethylaniline,N,N-diethylaniline, benzyldimethylamine, pyridine, substitutedpyridines, such as picolines, lutidines, collidines or methyl ethylpyridines, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine,N,N'-dimethylpiperazine, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]undec-7-ene, alsotetramethylhexamethylenediamine, tetramethylethylenediamine,tetramethylpropylenediamine, tetramethylbutylenediamine, as well as1,2-dimorpholylethane, pentamethyldiethylenetriamine,pentaethyldiethylenetriamine, pentamethyldipropylenetriamine,tetramethyldiaminomethane, tetrapropyldiaminomethane,hexamethyltriethylenetetramine, hexamethyltripropylenetetramine,diisobutylenetriamine or triisopropylenetetramine.

Particularly favorable reactive SO₃ derivatives are: (CH₃)₃ N.SO₃, (C₂H₅)₃ N.SO₃, pyridine.SO₃, 2-picoline.SO₃, 2,6-lutidine.SO₃ andcollidine.SO₃. The adduct HCON(CH₃)₂.SO₃, for example, can also be usedsuccessfully.

It is also possible to produce the adducts in situ.

Although, in principle, it is possible to carry out the reactionaccording to the invention without a solvent, nevertheless it ispreferable to carry it out in an inert inorganic or organic solvent.Suitable inert inorganic or organic solvents are those liquids which donot react in an undesired manner with SO₃ or its reactive derivatives orwith acetoacetamide or the final product of the reaction. Thus, becauseof the considerable reactivity of, in particular, SO₃ and its reactiveadducts, only relatively few solvents are suitable for this purpose.

Preferred solvents are:

Inorganic solvents: liquid SO₂ ;

organic solvents: halogenated aliphatic hydrocarbons, preferably havingup to 4 carbon atoms, such as, for example, methylene chloride,chloroform, 1,2-dichloroethane, trichloroethylene, tetrachloroethylene,chloroethylene, trichlorofluoroethylene etc.;

esters of carbonic acid with lower aliphatic alcohols, preferably withmethanol or ethanol;

nitroalkanes, preferably having up to 4 carbon atoms, in particularnitromethane;

pyridine and alkyl-substituted pyridine, preferably collidine; and

aliphatic sulfones, preferably sulfolane.

The organic solvents can be used either alone or in a mixture.

Particularly preferred organic solvents are: methylene chloride,chloroform, 1,2-dichloroethane, dimethyl carbonate, nitromethane andcollidine.

The amount of inert solvent used is not critical. When a solvent isused, it is merely necessary to ensure adequate solution of thereactants; the upper limit of the amount of solvent is determined byeconomic considerations.

The reaction temperature is normally between about -70° and +180° C.,preferably between about -40° and +90° C.

The reaction is normally carried out under atmospheric pressure.

The reaction time can be between a few minutes (at higher temperatures)and a few days (in the lower temperature range).

The reaction can be carried out in such a manner that theacetoacetamide, where appropriate in solution, is initially introducedand SO₃, or the reactive SO₃ adduct, where appropriate in the dissolvedform, is metered in, or both reactants are simultaneously transferredinto the reaction chamber, or SO₃, or its reactive derivatives, isinitially introduced and acetoacetamide is fed in, or, for example,acetoacetamide is initially treated with about 1 to 5 moles, preferablywith about 1 to 2 moles, of a reactive SO₃ derivative (per mole ofacetoacetamide) for about 20 minutes to 48 hours, preferably about 30minutes to 24 hours, at about -30° to -180° C., preferably at about 0°to 90° C., and this solution is metered into the SO₃.

The acetoacetamide is preferably initially reacted with a reactive SO₃derivative. Subsequently, part of the SO₃ is initially introduced andthen, either continuously or in portions, both the reaction solution ofacetoacetamide and the reactive SO₃ derivative, together with SO₃, aremetered in.

After completion of the reaction, the mixture is normally stirredfurther for about half an hour up to several hours.

The reaction mixture is worked up in a customary manner. In the casewhere inert organic solvents (which are immiscible with water) are usedas the reaction medium, the working up can be carried out as follows,for example: to the solution containing SO₃ are added about 10 times themolar amount (based on SO₃) of ice or water. This brings about phaseseparation: the 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxidewhich has formed is present mainly in the organic phase. The fractionsstill present in the aqueous sulfuric acid can be obtained by extractionwith an organic solvent such as, for example, methylene chloride orethyl acetate. The combined organic phases are then, for example, driedwith sodium sulfate and evaporated. If it is intended to obtain the freecompound, it is purified in a customary manner (preferably bycrystallization). The yield is between about 30 and 90% of theory basedon acetoacetamide.

However, if it intended to obtain a non-toxic salt of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide, this isfollowed by neutralization with a base. For this purpose, it isadvantageous to neutralize, using an appropriate base, preferably usinga potassium base such as, for example KOH, KHCO₃, K₂ CO₃, K alcoholatesetc., the organic phases which have been combined, dried and evaporatedduring the course of the working up of the reaction mixture and are insuitable organic solvents such as, for example, alcohols, ketones,esters or ethers, or in water. The oxathiazinone salt then precipitatesout in the form of crystals, where appropriate after evaporation of thesolution, and can also be recrystallized for purification.

The yield in the neutralization step is virtually 100%.

The Examples which follows are intended to illustrate the inventionfurther. The (invention) examples are followed by a comparison examplewhich shows that acetoacetamide-N-sulfonic acid does not cyclize withagents which eliminate water other than SO₃, in this case P₂ O₅.

EXAMPLE 1

5.1 g (50 mmol) of acetoacetamide in 50 ml of CH₂ Cl₂ were addeddropwise to 8 ml (200 mmol) of liquid SO₃ in 50 ml of CH₂ Cl₂ at -60° C.After 2 hours, 50 ml of ethyl acetate and 50 ml of water were added tothe solution. The organic phase was separated off, and the aqueous phasewas extracted twice more with ethyl acetate. The combined organic phaseswere dried over sodium sulfate, evaporated, and the residue wasdissolved in methanol. On neutralization of the solution with methanolicKOH, the potassium salt of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one,2,2-dioxide precipitated out.

Yield: 3.1 g=31%.

EXAMPLE 2

15.9 g (100 mmol) of the pyridine .SO₃ complex and 5.1 g (50 mmol) ofacetoacetamide in 100 ml of CH₂ Cl₂ were stirred at room temperature for17 hours. The mixture was then added dropwise, within 10 minutes, to asolution of 12 ml (300 mmol) of SO₃ in 50 ml of CH₂ Cl₂ at -30° C. 20Minutes later, the mixture was worked up as in Example 1.

Yield: 7.9 g=79%.

EXAMPLE 3

A solution of 4 ml (100 mmol) of SO₃ in 20 ml of CH₂ Cl₂ was addeddropwise to 13.2 ml (110 mmol) of 2,4,6-collidine in 50 ml of CH₂ Cl₂ at-40° C. The solution was then stirred with 9.1 g (90 mmole) ofacetoacetamide at room temperature for 23 hours. This solution was addeddropwise, within 1 hour, to 4.4 ml (110 mmol) of SO₃ in 200 ml of CH₂Cl₂ at -30° C. Over the same period, 4.4 ml portions (110 mmol) of SO₃were added after 12, 24, 36 and 48 minutes. 20 Minutes later, themixture was worked up as in Example 1, with the addition of 90 ml of H₂O.

Yield: 11.8 g=65%.

EXAMPLE 4

A solution of 4 ml (100 mmol) of SO₃ in 20 ml of CH₂ Cl₂ was addeddropwise to 15.2 ml (110 mmol) of triethylamine in 50 ml of1,2-dichloroethane at -40° C. The solution was boiled with 5.1 g (50mmol) of acetoacetamide for 4 hours. It was then cooled at -30° C.,added dropwise, within 1 hour, to a solution of 2.4 ml (60 mmol) of SO₃in 50 ml of CH₂ Cl₂. Over the same period, 2.4 ml portions (60 mmol) ofSO₃ were added after 12, 24, 36 and 48 minutes. 20 Minutes later, themixture was worked up as in Example 1.

Yield: 1 g=10%.

EXAMPLE 5

A solution of 4 ml (100 mmol) of SO₃ in 20 ml of CH₂ Cl₂ was addeddropwise to 13.2 ml (110 mmol) of 2,4,6-collidine in 50 ml of CH₂ Cl₂ at-40° C. After addition of 5.1 g (50 mmol) of acetoacetamide, the mixturewas stirred at room temperature for 17 hours. This solution was addeddropwise, within 1 hour, to a solution of 2.4 ml (60 mmol) of SO₃ in 50ml of CH₂ Cl₂ at -30° C. Over the same period, 2.4 ml portions (60 mmol)of SO₃ were added after 12, 24, 36 and 48 minutes. 20 Minutes later, themixture was worked up as in Example 1.

Yield: 9 g=90%.

EXAMPLE 6

A solution of 5.1 g (50 mmol) of acetoacetamide and 6.9 ml oftriethylamine in 100 ml of CH₂ Cl₂ were added dropwise, within 60minutes, to 8 ml (200 mmol) of liquid SO₃ in 150 ml of CH₂ Cl₂ at -25°C., and the mixture was then stirred at -25° C. for 90 minutes. Theworking up was carried out as in Example 1.

Yield: 4.1 g=41%.

EXAMPLE 7

The process was carried out as in Example 6, but 16 g (200 mmol) ofsolid SO₃ were used in place of 8 ml (200 mmol) of liquid SO₃.

Yield: 3.7 g=37%.

EXAMPLE 8

A solution of 5.1 g (50 mmol) of acetoacetamide in 100 ml of CH₂ Cl₂ wasadded dropwise, within 30 minutes, to a mixture of 15.5 ml (250 mmolSO₃) of 65% oleum in 150 ml of CH₂ Cl₂ at -25° C., and the mixture wasthen stirred at -25° C. for 60 minutes. The working up was carried outas in Example 1.

Yield: 2.3 g=23%.

COMPARISON EXAMPLE

35.42 g (250 mmol) of P₂ O₅ were initially introduced into 250 ml of CH₂Cl₂. At -25° C., 62.5 ml of acetoacetamide-N-sulfonic acid solution inCH₂ Cl₂, containing 0.05 mole of the sulfonic acid (yields 9 g), wereadded dropwise within 60 minutes. After a further 60 minutes at -25° C.,the mixture was worked up as in Example 1. No6-methyl-3,4-dihydro-1,2,3-oxathiazin-4one 2,2-dioxide or its potassiumsalt could be detected in the reaction product by thin-layerchromatography.

We claim:
 1. A process for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts, which comprises reacting acetoacetamide with at leastapproximately twice the molar amount of SO₃ in an inert inorganic ororganic solvent.
 2. The process as claimed in claim 1, wherein theamount of SO₃ used is about 2 to 20 moles per mole of acetoacetamide. 3.The process as claimed in claim 2, wherein the amount of SO₃ used isabout 4 to 10 moles per mole of acetoacetamide.
 4. The process asclaimed in claim 1, wherein part of the SO₃ is used in the form ofreactive derivatives.
 5. The process as claimed in claim 4, wherein thereactive derivatives are tertiary amines.
 6. The process as claimed inclaim 1, wherein the inert inorganic solvent used is liquid SO₂ and theinert organic solvent used is at least one solvent from the followinggroup: halogenated aliphatic hydrocarbons; esters of carbonic acid withlower aliphatic alcohols; nitroalkanes; pyridine and alkyl-substitutedpyridines and aliphatic sulfones.
 7. The process as claimed in claim 6,wherein the inert inorganic solvent is a halogenated aliphatichydrocarbon having up to 4 carbon atoms; an ester of carbonic acid withmethanol or ethanol; a nitroalkane having up to 4 carbon atoms;pyridine; collidine; or sulfolane.
 8. The process as claimed in claim 1,wherein the inert organic solvent used is at least one of the followingsolvents: ethylene chloride, chloroform, 1,2-dichloroethane, dimethylcarbonate, nitromethane and collidine.
 9. The process as claimed inclaim 1, wherein the reaction is carried out at temperatures betweenabout -70° and +180° C.
 10. The process as claimed in claim 9, whereinthe reaction is carried out at temperatures between about -40° and +90°C.
 11. The process as claimed in claim 1 including the further step ofneutralizing with a base the 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4one2,2-dioxide which is produced in the form of the acid in this reactionin order to obtain the non-toxic salts.
 12. The process as claimed inclaim 11, wherein the base used for the neutralization of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide is a potassiumbase.